4-pregenen-11beta-17-21-triol-3,20-dione derivatives

ABSTRACT

The present invention relates to novel 4-pregenen-11β-17-21-triol-3,20-dione derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals, as modulators of glucocorticoid or mineralocorticoid receptors. The invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with glucocorticoid or mineralocorticoid receptor modulation.

RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/533,847, filed Nov. 5, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/673,623, filed Nov. 9, 2012, now U.S. Pat. No.8,906,892, issued Dec. 9, 2014, which claims the benefit of U.S.Provisional Application Ser. No. 61/558,775, filed Nov. 11, 2011, thedisclosures of which are hereby incorporated by reference in theirentireties and serve as the basis of a priority and/or benefit claim forthe present application.

FIELD OF THE INVENTION

The present invention relates to novel4-pregenen-11β-17-21-triol-3,20-dione derivatives, processes forpreparing them, pharmaceutical compositions containing them and theiruse as pharmaceuticals, as modulators of glucocorticoid ormineralocorticoid receptors. The invention relates specifically to theuse of these compounds and their pharmaceutical compositions to treatdisorders associated with glucocorticoid or mineralocorticoid receptormodulation.

BACKGROUND OF THE INVENTION

Glucocorticoid (GC) agonists represent a class of anti-inflammatorycompounds that are useful in treating multiple ocular conditionsincluding elevated intraocular pressure, glaucoma, uveitis, retinal veinocclusions, macular degeneration, diabetic retinopathy, various forms ofmacular edema, post-surgical inflammation, inflammatory conditions ofthe palpebral and bulbar conjunctiva, cornea, and anterior segment ofthe globe, such as allergic conjunctivitis, ocular rosacea, dry eye,blepharitis, retinal detachment, meibomian gland dysfunction (MGD),superficial punctate keratitis, herpes zoster keratitis, iritis,cyclitis, selected infective conjunctivitis, corneal injury fromchemical, radiation, or thermal burns, penetration of foreign bodies,allergy, or combinations thereof.

A potential use limiting and sight-threatening side-effect oftraditional GC agonist therapies (e.g. fluocinolone acetonide) is ocularhypertension that is likely generated by an increased resistance ofaqueous humor flow through the trabecular meshwork. The mechanism of GCagonist-induced outflow resistance and subsequent ocular hypertension isnot well understood.

As such, GC modulation through agonist or antagonist activity of GCreceptors that does not result in increased intraocular pressure orother side effects is needed in the art and is described herein.

SUMMARY OF THE INVENTION

The present invention relates to novel4-pregenen-11β-17-21-triol-3,20-dione derivatives useful in treating oneor more ocular conditions. Methods of treating one or more ocularconditions are also disclosed. Ocular conditions treated using compoundsand/or formulations described herein include, but are not limited to,elevated intraocular pressure, glaucoma, uveitis, retinal veinocclusions, macular degeneration, diabetic retinopathy, various forms ofmacular edema, post-surgical inflammation, inflammatory conditions ofthe palpebral and bulbar conjunctiva, cornea, and anterior segment ofthe globe, such as allergic conjunctivitis, ocular rosacea, dry eye,blepharitis, retinal detachment, meibomian gland dysfunction (MGD),superficial punctate keratitis, herpes zoster keratitis, iritis,cyclitis, selected infective conjunctivitis, corneal injury fromchemical, radiation, or thermal burns, penetration of foreign bodies,allergy, or combinations thereof.

In one aspect, the invention therefore provides a compound of Formula I,its enantiomers, diastereoisomers, hydrates, solvates, crystal forms andindividual isomers, tautomers or a pharmaceutically acceptable saltthereof,

wherein:R¹ is optionally substituted C₇-C₁₁ alkyl, optionally substituted C₂-C₈alkenyl, optionally substituted C₂-C₈ alkynyl, optionally substituted C₄or C₆₋₈ cycloalkyl, optionally substituted aryl, substituted benzyl,optionally substituted heterocycle, optionally substituted C₃-C₁₀cycloalkenyl, optionally substituted C₅-C₁₀ cyclodiene, optionallysubstituted O(C₃-C₆) alkyl, amino groups, sulfonamide groups, amidegroups, except phenyl.

In another embodiment, the invention therefore provides a compound ofFormula I, wherein R¹ is selected from:

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 7 to 11 carbon atoms. One methylene(—CH₂—) group, of the alkyl group can be replaced by oxygen, sulfur,sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate,amide, sulfonamide, by a divalent C₃₋₈ cycloalkyl, by a divalentheterocycle, or by a divalent aryl group. Alkyl groups can beindependently substituted by halogen atoms, hydroxyl groups, cycloalkylgroups, amino groups, heterocyclic groups, aryl groups, carboxylic acidgroups, ester groups, ketone groups, phosphonic acid groups, sulphonicacid groups, phosphoric acid groups, nitro groups, amide groups,sulfonamide groups.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 4, and 6 to 8 carbon atoms derived from a saturatedcyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be independently substituted by halogen atoms, sulfonylC₁₋₈ alkyl groups, sulfoxide C₁₋₈ alkyl groups, sulfonamide groups,nitro groups, cyano groups, —OC₁₋₈ alkyl groups, —SC₁₋₈ alkyl groups,—C₁₋₈ alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketonegroups, alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkylgroups or hydroxyl groups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 10 carbon atoms derived from a saturatedcycloalkyl having at least one double bond. Cycloalkenyl groups can bemonocyclic or polycyclic. Cycloalkenyl groups can be independentlysubstituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitrogroups, cyano groups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₆alkyl groups, —C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups,alkylamino groups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups orhydroxyl groups.

The term “cyclodiene”, as used herein, refers to a monovalent ordivalent group of 5 to 10 carbon atoms derived from a saturatedcycloalkyl having two double bonds. Cyclodiene groups can be monocyclicor polycyclic. Cyclodiene groups can be independently substituted byhalogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyanogroups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₆ alkyl groups,—C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups, alkylaminogroups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxylgroups.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 8 carbon atoms, derived from a saturatedalkyl, having at least one double bond. One methylene (—CH₂—) group, ofthe alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. C₂₋₈ alkenyl can be in the E or Z configuration. Alkenylgroups can be substituted by alkyl groups, as defined above or byhalogen atoms.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 8 carbon atoms, derived from a saturatedalkyl, having at least one triple bond. One methylene (—CH₂—) group, ofthe alkynyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. Alkynyl groups can be substituted by alkyl groups, asdefined above, or by halogen atoms.

The term “heterocycle” as used herein, refers to a 3 to 10 member ring,which can be aromatic or non-aromatic, saturated or unsaturated,containing at least one heteroatom selected form oxygen, nitrogen,sulfur, or combinations of at least two thereof, interrupting thecarbocyclic ring structure. The heterocyclic ring can be interrupted bya C═O; the S and N heteroatoms can be oxidized. Heterocycles can bemonocyclic or polycyclic. Heterocyclic ring moieties can be substitutedby halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyanogroups, —OC₁₋₆ alkyl groups, —SC₁₋₆ alkyl groups, —C₁₋₈ alkyl groups,—C₂₋₆ alkenyl groups, —C₂₋₆ alkynyl groups, ketone groups, alkylaminogroups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxylgroups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms, by removal of one hydrogen atom. Aryl can be substituted byhalogen atoms, sulfonyl C₁₋₆ alkyl groups, sulfoxide C₁₋₆ alkyl groups,sulfonamide groups, carbocyclic acid groups, C₁₋₈ alkyl carboxylates(ester) groups, amide groups, nitro groups, cyano groups, —OC₁₋₆ alkylgroups, —SC₁₋₆ alkyl groups, —C₁₋₆ alkyl groups, —C₂₋₆ alkenyl groups,—C₂₋₆ alkynyl groups, ketone groups, aldehydes, alkylamino groups, aminogroups, aryl groups, C₃₋₈ cycloalkyl groups or hydroxyl groups. Arylscan be monocyclic or polycyclic.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “ketone” as used herein, represents an organic compound havinga carbonyl group linked to a carbon atom such as —(CO)R^(x) whereinR^(x) can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle asdefined above.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y)”,wherein R^(x) and R^(y) can be the same or independentlyhydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as definedabove.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula “—SO₂⁻”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “sulfonate” as used herein, represents a group of the formula“—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “nitro” as used herein, represents a group of formula “—NO₂”.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y),” wherein R^(x) and R^(y) can be the same orindependently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl,heterocycle as defined above.

The term “ester” as used herein, represents a group of formula“—C(O)OR^(x),” wherein R^(x) is alkyl, aryl, cycloalkyl, cycloalkenyl,heterocycle as defined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl,heterocycle as defined above.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—OP(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

-   -   The formula “H”, as used herein, represents a hydrogen atom.    -   The formula “O”, as used herein, represents an oxygen atom.    -   The formula “N”, as used herein, represents a nitrogen atom.    -   The formula “S”, as used herein, represents a sulfur atom.

Compounds of the invention are:

(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl(4-bromophenyl)acetate;(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl3-(phenylsulfonyl)propanoate,(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl2-furoate.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, such as for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid and the like; or an organic acid such as for example,acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaricacid, maleic acid, oxalic acid, tartaric acid, succinic acid, malicacid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric,methylsulfonic, ethanesulfonic, benzenesulfonic, formic and the like(Handbook of Pharmaceutical Salts, P. Heinrich Stahl & Camille G.Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).

The base addition salt form of a compound of Formula I that occurs inits acid form can be obtained by treating the acid with an appropriatebase such as an inorganic base, for example, sodium hydroxide, magnesiumhydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like;or an organic base such as for example, L-Arginine, ethanolamine,betaine, benzathine, morpholine and the like. (Handbook ofPharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds),Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically. Compounds according to thepresent invention may exist in different polymorphic forms. Although notexplicitly indicated in the above formula, such forms are intended to beincluded within the scope of the present invention.

The compounds described herein are useful in treating a variety ofocular conditions including, but not limited to elevated intraocularpressure, glaucoma, uveitis, retinal vein occlusions, maculardegeneration, diabetic retinopathy, various forms of macular edema,post-surgical inflammation, inflammatory conditions of the palpebral andbulbar conjunctiva, cornea, and anterior segment of the globe, such asallergic conjunctivitis, ocular rosacea, dry eye, blepharitis, retinaldetachment, meibomian gland dysfunction (MGD), superficial punctatekeratitis, herpes zoster keratitis, iritis, cyclitis, selected infectiveconjunctivitis, corneal injury from chemical, radiation, or thermalburns, penetration of foreign bodies, allergy, or combinations thereof.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of the glucocorticoidreceptors (GR) and/or the mineralocorticoid receptors (MR). receptors.Such methods can be performed, for example, by administering to asubject in need thereof a therapeutically effective amount of at leastone compound of the invention, or any combination thereof, orpharmaceutically acceptable salts, hydrates, solvates, crystal forms andindividual isomers, enantiomers, and diastereomers thereof.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier. The compounds described herein may be administeredat pharmaceutically effective dosages. Such dosages are normally theminimum dose necessary to achieve the desired therapeutic effect.Generally, such doses will be in the range of about 1 mg/day to about1000 mg/day; more preferably in the range of about 10 mg/day to about500 mg/day. In another example embodiment, the compound or compounds maybe present in a composition or formulation in a range of about 0.5mg/kg/day to about 100 mg/kg/day or about 1 mg/kg/day to about 100mg/kg/day. However, the actual amount of the compound to be administeredin any given case will be determined by a physician taking into accountthe relevant circumstances, such as the age and weight of the patient,the patient's general physical condition, the severity of ocularcondition, and the route of administration. In some instances, dosing isevaluated on a case-by-case basis.

In another example embodiment, provided are pharmaceutical compositionsincluding at least one compound in a pharmaceutically acceptablecarrier. Pharmaceutical compositions can be used in the form of a solid,a solution, an emulsion, a dispersion, a micelle, a liposome, and thelike, wherein the resulting composition contains one or more compoundsdescribed herein, as an active ingredient, in admixture with an organicor inorganic carrier or excipient suitable for enteral or parenteralapplications. One or more compounds may be combined, for example, withthe usual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, suppositories, solutions, emulsions, suspensions, andany other form suitable for use. The carriers which can be used includeglucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Compoundsdescribed herein are included in pharmaceutical compositions in anamount sufficient to produce the desired effect upon the process ordisease condition.

In another embodiment, the compounds described herein can beadministered orally in any acceptable form, such as a tablet, liquid,capsule, powder and the like. However, other routes may be desirable ornecessary, particularly if the patient suffers from nausea. Such otherroutes may include, without exception, transdermal, parenteral,subcutaneous, intranasal, intrathecal, intramuscular, intravenous, andintrarectal modes of delivery. Additionally, formulations may bedesigned to delay release of the active compound over a given period oftime, or to carefully control the amount of drug released at a giventime during the course of therapy.

Pharmaceutical compositions in a form suitable for oral use, forexample, are administered as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups or elixirs. Compositions intended for oral use maybe prepared according to any method known to the art for the manufactureof pharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of a sweetening agentsuch as sucrose, lactose, or saccharin, flavoring agents such aspeppermint, oil of wintergreen or cherry, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets containing compounds described herein in admixturewith non-toxic pharmaceutically acceptable excipients may also bemanufactured by known methods.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug. The actual amount of the compound to be administeredin any given case will be determined by a physician taking into accountthe relevant circumstances, such as the severity of the condition, theage and weight of the patient, the patient's general physical condition,the cause of the condition, and the route of administration. Describedherein are compounds capable of modulating glucocorticoid receptors (GR)and/or mineralocorticoid receptors (MR). The compounds described canhave greater GR activation and/or binding potency compared to a compoundsuch as cortisol. As such, the compounds can efficiently treat ocularindications. The compounds can further be metabolized by esteraseenzymes within the eye to form the natural agonist cortisol, therebyreducing the risk of ocular hypertension. The cortisol remaining withinthe eye and body is further metabolized to inactive compounds vianaturally occurring dehydroxylases and other enzymes making this a safetherapeutic approach.

In patients, the naturally occurring endogenous GC agonist cortisol(hydrocortisone) has a minimal effect on intraocular pressure whenapplied locally via eye drops compared to synthetic GCs such asdexamethasone, prednisolone, and fluorometholone (Cantrill et al.,1975). Further support of the overall superior safety of cortisol as atherapeutic is the fact that various topical hydrocortisone formulationsare currently sold over the counter directly to consumers.

Without wishing the bound to any particular theory, it was surprisinglydiscovered that the presently described compounds can have moreglucocorticoid receptor modulation than cortisol because of themodification to the 17-position of the cortisol molecule.

As used herein, the term “therapeutically effective amount” means theamount of the pharmaceutical composition that will elicit the biologicalor medical response of a subject in need thereof that is being sought bythe researcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The excipients used may be, for example, (1) inert diluents such ascalcium carbonate, lactose, calcium phosphate or sodium phosphate; (2)granulating and disintegrating agents such as corn starch, potato starchor alginic acid; (3) binding agents such as gum tragacanth, corn starch,gelatin or acacia, and (4) lubricating agents such as magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the compounds are mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin.They may also be in the form of soft gelatin capsules wherein thecompounds are mixed with water or an oil medium, for example, peanutoil, liquid paraffin, or olive oil.

The compounds described herein can also be administered as anophthalmically acceptable formulation or composition. A liquid which isophthalmically acceptable is formulated such that it can be administeredtopically to the eye. The comfort should be maximized as much aspossible, although sometimes formulation considerations (e.g. stability)may necessitate less than optimal comfort. In the case that comfortcannot be maximized, the liquid should be formulated such that theliquid is tolerable to the patient for topical ophthalmic use.Additionally, an ophthalmically acceptable liquid should either bepackaged for single use, or contain a preservative to preventcontamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in ophthalmic compositions describedherein include, but are not limited to, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuricnitrate. A useful surfactant is, for example, Tween 80. Likewise,various useful vehicles may be used in the ophthalmic preparationsdescribed herein. These vehicles include, but are not limited to,polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In one example embodiment, an ophthalmic composition as described hereinmay have ingredients used in the following amounts listed in Table 1.

TABLE 1 Ingredient Amount (% w/v) active ingredient about 0.001-5preservative   0-0.10 vehicle 0-40 tonicity adjustor 1-10 buffer0.01-10   pH adjustor q.s. pH 4.5-7.5 antioxidant as needed surfactantas needed purified water as needed to make 100%

In other embodiments, the ophthalmically acceptable liquid can beformulated for intraocular injection. The compounds described herein canbe formulated as a liquid, gel paste, or the like for intraocularinjection. Further, the compounds can be formulated into sustainedrelease or controlled release intraocular implants comprisingbiodegradable polymers such as polylactic acid, poly glycolic acid,combinations thereof and the like.

Some exemplary compositions can include a combination of two or morecompounds as described herein. Different ratios of compounds can beformulated depending on a particular ocular condition or set ofconditions being treated.

Since individual subjects may present a wide variation in severity ofsymptoms and each composition has its unique therapeuticcharacteristics, the precise mode of administration and dosage employedfor each subject is left to the discretion of the practitioner.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of Formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The synthetic scheme set forth below, illustrate howcompounds according to the invention can be made.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of protium ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diastereoisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 12.0; and Intermediatesand reagent names used in the examples were generated with software suchas Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw2.5 SP1.

In general, characterization of the compounds is performed according tothe following methods:

NMR spectra are recorded on 300 and/or 600 MHz Varian and acquired atroom temperature. Chemical shifts are given in ppm referenced either tointernal TMS or to the solvent signal.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, AK Scientific, AmFine Com, Carbocore,Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific,SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; howeversome known intermediates, were prepared according to publishedprocedures.

Usually the compounds of the invention were purified by columnchromatography (Auto-column) on an Teledyne-ISCO CombiFlash with asilica column, unless noted otherwise.

Example 1 Intermediate 1 2-(Trimethoxymethyl)furan

An anhydrous solution of HCl in methanol was prepared by slowly addingacetyl chloride (10.5 mL) to methanol (20 mL) at room temperature. Thesolution was stirred 2 h. After cooling in an ice bath under nitrogen,2-furonitrile (12 mL, 137 mM) was added by syringe. The reaction wasstirred in a dry atmosphere at 0° C. overnight. After warming to roomtemperature the intermediate was precipitated by the addition of dryether (50 mL). It was filtered out in a dry sintered glass funnel in adry box and washed with dry ether. After ether evaporation the solid wastreated with dry methanol and stirred at 50° C. for 70 h. The mixturewas treated with dry ether (60 mL) and ammonium chloride was removed byfiltration through a dry sintered glass funnel. Concentration of thefiltrate gave the title compound (6 g) as a colorless oil.

Example 2 Intermediate 2rel-(8R,9R,10S,11R,13R,14R,17S)-2′-(2-furyl)-11-hydroxy-2′-methoxy-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-5′H-spiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxane]-3,5′(2H)-dione

A solution of cortisol (10.4 g, approximately 28 mM), dried byevaporation from ethanol-butanol) in dry tetrahydrofuran (40 mL) wastreated with crude Intermediate 1 (5.4 g, 32 mM) and 0.5 mL of asolution of anhydrous p-toluenesulfonic acid in toluene (approximately0.7 M). The reaction was stirred at room temperature 48 h. Additionaldry THF was added (100 mL) and anhydrous p-TSA solution (2 mL), and thereaction was stirred 48 h. The reaction was partially concentrated andstirred another night. The reaction was partitioned between ethylacetate and aqueous dibasic sodium phosphate. The organic layer waswashed with brine, dried, and evaporated. The residue was purified bychromatography (silica gel, 30-70 ethyl acetate-dichloromethane) andgave Intermediate 2 (0.9 g).

Example 3 Compound 1(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl2-furoate

Intermediate 1 was dissolved in tetrahydrofuran (20 mL) and cooled inand ice/salt water bath under an inert atmosphere. The solution wastreated with 0.37 mL of a 1M aqueous sulfuric acid solution. Thereaction was stirred cold for 2 h. The reaction worked up with dibasicsodium phosphate solution and ethyl acetate. The ethyl acetate solutionwas washed with brined, dried and evaporated. The product was purifiedby chromatography (silica gel 60, 50-50 ethyl acetate-dichloromethane)and concentrated. The residue was crystallized fromdichloromethane-hexane to give Compound 1 (1.9 g, 82%).

NMR (CDCl₃, TMS): δ 1.00 (s, 3H), 1.13 (m, 3H), 1.47 (s, 3H), 1.51 (m,1H), 2.54-1.74 (m's, 13H), 2.90 (m, 1H), 3.08 (m, 1H), 4.37 (m, 2H),4.56 (m, 1H), 5.71 (s, 1H), 6.54 (m, 1H), 7.20 (m, 1H), 7.61 (m, 1H).

Example 4 Intermediate 3 Methyl 2-(4-bromophenyl) acetimidatehydrochloride

In a manner similar to that described in Example 1, 2-(4-bromophenyl)acetonitrile is converted to Intermediate 3. The residue that wasobtained was not treated with methanol but isolated to give Intermediate3.

Example 5 Intermediate 4rel-(8R,9R,10S,11R,13R,14R,17S)-2′-(4-bromobenzyl)-11-hydroxy-2′-methoxy-10,13-dimethyl-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-5′H-spiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxane]-3,5′(2H)-dione

In a manner similar as described in Example 2, cortisol and Intermediate3 were converted to Intermediate 4. Purification by silica gel flashchromatography (20% ethyl acetate in CH₂Cl₂ elution) provided the 24.8mg of Intermediate 4: ICMS-ESI (m/z): calculated for, C₃₀H₃₇BrO₆, 572,574, [M+H]⁺. found 573, 575.

Example 6 Compound 2 (8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl(4-bromophenyl)acetate

In a manner similar as described in Example 3, Intermediate 4 wasconverted to Compound 2. Purification of the crude reaction mixture bysilica gel chromatography (20% ethyl acetate, methylene chloride)provided the 57.7 mg of Compound 2. ICMS-ESI (m/z): calculated for,C₂₉H₃₅BrO₆, 558, 560; [M+H]⁺. found 559, 561.

Example 7 Intermediate 5rel-(8R,9R,10S,11R,13R,14R,17S)-2′-ethoxy-11-hydroxy-10,13-dimethyl-2′-[2-(phenylsulfonyl)ethyl]-1,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-5′H-spiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxane]-3,5ζ(2H)-dione

In a manner similar as described in Example 2, cortisol and((3,3,3-trimethoxypropyl)sulfonyl)benzene were converted to Intermediate5. Purification of the crude reaction mixture by silica gelchromatography (20% ethyl acetate, methylene chloride) provided the 13.1mg of Intermediate 5. ICMS-ESI (m/z): calculated for, C₃₂H₄₂O₈S, 586;[M+H]⁺. found 587.

Example 8 Compound 3(8S,9S,10R,11S,13S,14S,17R)-17-glycoloyl-11-hydroxy-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl3-(phenylsulfonyl)propanoate

In a manner similar to experiment described in Example 3, Intermediate 5was converted to the title compound. Purification of the crude reactionmixture by silica gel chromatography (20% ethyl acetate, methylenechloride) provided the 96.9 mg of Compound 3. ICMS-ESI (m/z): calculatedfor C₃₀H₃₈O₆S, 558; [M+H]⁺. found 559.

Example 9 Glucocorticoid Receptor Transactivation Potencies for Cortisoland 17-Ester Derivatives

Glucocorticoid receptor (GR) activation potency was assessed using aHeLa cell line containing the MMTV-bla reporter (MMTV-bla HeLaCELLSENSOR®, Invitrogen Corp., Carlsbad, Calif.). This cell line wasstably transfected with an expression construct containing β-lactamasecDNA under control of the MMTV response element previously identified asa glucocorticoid receptor response element. Results from one experimentperformed in duplicate for the compounds and the control compound,dexamethasone, are summarized in Table 2. All assays were performed as10-point dose responses using a half log-fold dilution series startingwith a maximum compound concentration of 100 nM. The compounds wereincubated for 5 hours. The activation of endogenous GR leads toexpression of the reporter β-lactamase which is detected by theconversion of a FRET substrate in a ratiometric assay format. Thisfunctional assay allows for measurement of receptor agonism by compoundsand can be used to determine compound potency and selectivity. Assayreproducibility was determined by calculating Z′ values for untreatedversus maximum stimulation. The Z′ value was greater than 0.6,indicating good reproducibility of the assay format.

Several compounds showed dose-dependent stimulation of the GR signalingpathway (Table 2). Two compounds, cortisol 17-cyclopentanoate andcortisol 17-benzoate, showed about 30-fold greater potency compared tothe parent molecule cortisol.

TABLE 2 Glucocorticoid receptor potency. Shown are the EC₅₀ (nM) and Z′values for the control compound, dexamethasone, and the compounds testedin agonist mode. EC50 % Activation Compound (nM) GR at 100 nM Z′

1.05 Control Compound 0.87

41.6 43 0.87

>100 17 0.87

— 0 0.87

Example 10 Mineralocorticoid Receptor Transactivation Potencies forCortisol and 17-Ester Derivatives

Mineralocorticoid receptor (MR) activation potency was assessed using aHEK 293T cell line containing the UAS-bla reporter (UAS-bla HEK 293TCELLSENSOR®). This cell line was stably cotransfected with an expressionconstruct containing β-m lactamase cDNA under control of the GAL4Upstream Activator Sequence (UAS) and another expression constructencoding for the fusion protein GAL4(DBD)-MR(LBD). Results for oneexperiment performed in duplicate for the novel compounds and thecontrol compound, aldosterone, in agonist mode are summarized in Table2. All assays were performed as 10-point dose responses using a halflog-fold dilution series starting with a maximum compound concentrationof 100 nM. The compounds were incubated for 16 hours. The activation ofthe fusion protein GAL4(DBD)-MR(LBD) leads to expression of the reporterβ-lactamase which is detected by the conversion of a FRET substrate in aratiometric assay format. This functional assay allows for measurementof receptor agonism by compounds and can be used to determine compoundpotency and selectivity. Assay reproducibility was determined bycalculating Z′ values for untreated versus maximum stimulation. The Z′value was greater than 0.6, indicating good reproducibility of the assayformat. Several compounds showed dose-dependent stimulation of the MRsignaling pathway (Table 3).

TABLE 2 Mineralocorticoid receptor potency. Shown are the EC₅₀ (nM) andZ′ values for the control compound, aldosterone, and the compoundstested in agonist mode. EC50 % Activation Compound (nM) GR at 100 nM Z′

0.47 Control Compound 0.77

2.90 75 0.77

3.48 79 0.77

5.53 77 0.77

Example 11 Treating Elevated Intraocular Pressure

A 58 year old male visits his ophthalmologist for a routine check-up.The physician discovers that the patient exhibits an elevatedintraocular pressure and is at high risk for future complications. Thepatient is instructed to apply a topical liquid formulation containingone of the compounds in Table 1 once daily to each eye.

The patient returns for a follow-up visit three months later. Uponmeasuring intraocular pressure, it is noted that the patient nowexhibits a reduced intraocular pressure.

Example 12 Treating Ocular Irritation

A 38 year old male visits his ophthalmologist complaining of irritationin his right eye.

The physician discovers that the patient's right eye is inflamed andred. The patient is instructed to apply a topical liquid formulationcontaining one of the compounds in Table 1 twice daily to the right eye.

The patient returns for a follow-up visit a week later. Upon inspectionof the right eye, it is noted that the patient's eye is no longer redand the patient indicates that the irritation is gone.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1. A pharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound having Formula I, or apharmaceutically acceptable salt, enantiomer, hydrate, or tautomerthereof,

wherein: R¹ is optionally substituted C₇-C₁₁ alkyl, optionallysubstituted C₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyloptionally substituted C₄ or C₆₋₈ cycloalkyl, optionally substitutedaryl, substituted benzyl, optionally substituted heterocycle, optionallysubstituted C₃-C₁₀ cycloalkenyl, optionally substituted C₅-C₁₀cyclodiene, optionally substituted O(C₃-C₆) alkyl, amino groups,sulfonamide groups, amide groups, except phenyl; and further comprisingone or more vehicles selected from the group consisting of polyvinylalcohol, povidone, hydroxypropyl methyl cellulose, poloxamers,carboxymethyl cellulose, hydroxyethyl cellulose and purified water. 2.The pharmaceutical composition according to claim 1 wherein R¹ is


3. The pharmaceutical composition according to claim 1 wherein R¹ issubstituted aryl.
 4. The pharmaceutical composition according to claim 1wherein R¹ is


5. The pharmaceutical composition according to claim 1 having astructure


6. The pharmaceutical composition according to claim 1 having astructure


7. The pharmaceutical composition according to claim 1 having astructure

8.-15. (canceled)
 16. The composition according to claim 4, wherein thecomposition further comprises one or more tonicity adjusters selectedfrom the group consisting of sodium chloride, potassium chloride,mannitol, and glycerin.
 17. The composition according to claim 4,wherein the composition further comprises one or more buffers selectedfrom the group consisting of acetate buffers, citrate buffers, phosphatebuffers, and borate buffers.
 18. The composition according to claim 4,wherein the composition further comprises one or more preservativesselected from the group consisting of benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuricnitrate.
 19. The composition according to claim 4, wherein thecomposition has a pH from about 4.5 to about 7.5.
 20. The compositionaccording to claim 16, wherein the composition further comprises one ormore buffers selected from the group consisting of acetate buffers,citrate buffers, phosphate buffers, and borate buffers.
 21. Thecomposition according to claim 20, wherein the composition furthercomprises one or more preservatives selected from the group consistingof benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuricacetate, and phenylmercuric nitrate.
 22. The composition according toclaim 20, wherein the composition has a pH from about 4.5 to about 7.5.23. The composition according to claim 21, wherein the composition has apH from about 4.5 to about 7.5.
 24. The composition according to claim4, wherein the one or more vehicles is selected from the groupconsisting of polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, and purified water; and wherein the composition furthercomprises one or more tonicity adjusters selected from the groupconsisting of sodium chloride and potassium chloride; and one or morebuffers selected from the group consisting of acetate buffers and boratebuffers; and wherein the composition has a pH from about 4.5 to about7.5.
 25. The composition according to claim 24, wherein the compositionfurther comprises one or more preservatives selected from the groupconsisting of benzalkonium chloride, chlorobutanol, thimerosal,phenylmercuric acetate, and phenylmercuric nitrate.
 26. The compositionaccording to claim 4, wherein the one or more vehicles is selected fromthe group consisting of polyvinyl alcohol, povidone, hydroxypropylmethyl cellulose, and purified water; and wherein the compositionfurther comprises one or more tonicity adjusters selected from the groupconsisting of sodium chloride and potassium chloride; and one or morebuffers selected from the group consisting of phosphate buffers andcitrate buffers; and wherein the composition has a pH from about 4.5 toabout 7.5.
 27. The composition according to claim 26, wherein thecomposition further comprises one or more preservatives selected fromthe group consisting of benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
 28. Thecomposition according to claim 4, wherein the one or more vehicles isselected from the group consisting of polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, and purified water; and wherein thecomposition further comprises one or more tonicity adjusters selectedfrom the group consisting of mannitol and glycerin; and one or morebuffers selected from the group consisting of phosphate buffers andcitrate buffers; and wherein the composition has a pH from about 4.5 toabout 7.5.
 29. The composition according to claim 28, wherein thecomposition further comprises one or more preservatives selected fromthe group consisting of benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.
 30. Thecomposition according to claim 4, wherein the one or more vehicles isselected from the group consisting of poloxamers, carboxymethylcellulose, hydroxyethyl cellulose, and purified water; and wherein thecomposition further comprises one or more tonicity adjusters selectedfrom the group consisting of sodium chloride and potassium chloride; andone or more buffers selected from the group consisting of acetatebuffers and borate buffers; and wherein the composition has a pH fromabout 4.5 to about 7.5.
 31. The composition according to claim 30,wherein the composition further comprises one or more preservativesselected from the group consisting of benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuricnitrate.
 32. The composition according to claim 4, wherein the one ormore vehicles is selected from the group consisting of poloxamers,carboxymethyl cellulose, hydroxyethyl cellulose, and purified water; andwherein the composition further comprises one or more tonicity adjustersselected from the group consisting of sodium chloride and potassiumchloride; and one or more buffers selected from the group consisting ofphosphate buffers and citrate buffers; and wherein the composition has apH from about 4.5 to about 7.5.
 33. The composition according to claim32, wherein the composition further comprises one or more preservativesselected from the group consisting of benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuricnitrate.
 34. The composition according to claim 4, wherein the one ormore vehicles is selected from the group consisting of poloxamers,carboxymethyl cellulose, hydroxyethyl cellulose, and purified water; andwherein the composition further comprises one or more tonicity adjustersselected from the group consisting of mannitol and glycerin; and one ormore buffers selected from the group consisting of phosphate buffers andcitrate buffers; and wherein the composition has a pH from about 4.5 toabout 7.5.
 35. The composition according to claim 34, wherein thecomposition further comprises one or more preservatives selected fromthe group consisting of benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, and phenylmercuric nitrate.